技术领域technical field
本发明属于化合物合成工艺技术领域，具体涉及一种盐酸利多卡因杂质E的制备方法。The invention belongs to the technical field of compound synthesis technology, and in particular relates to a preparation method of lidocaine hydrochloride impurity E.
背景技术Background technique
利多卡因(Lidocaine)是一种经多年临床应用的麻醉剂及抗心律失常药，由Lofgren于1934年合成，用作局部麻醉剂，它是可卡因的一种衍生物，但没有可卡因产生幻觉和上瘾的成分，局部麻醉效果较强而持久，有良好的表面穿透力，可注射也可作表面麻醉，一般施用一到三分钟后即生效，效果维持一到三小时。50年代开始用于治疗手术过程中出现的室性心律失常，1963年用于治疗心率失常，是目前防治急性心肌梗死及各种心脏病并发快速室性心律失常药物，是急性心肌梗死的室性早搏，室性心动过速及室性震颤的首选药。因此药具有安全有效、作用快等优点，广泛用于治疗各种原因引起的室性心律失常。此外，本品作为酰胺类局麻药及抗心律失常药，其麻醉作用是普鲁卡因的2倍。Lidocaine is an anesthetic and antiarrhythmic drug that has been clinically used for many years. It was synthesized by Lofgren in 1934 and is used as a local anesthetic. It is a derivative of cocaine, but it does not have hallucinations and addiction. Components, local anesthesia has strong and long-lasting effect, has good surface penetration, can be injected or used as topical anesthesia, and generally takes effect within one to three minutes after application, and the effect lasts for one to three hours. In the 1950s, it was used to treat ventricular arrhythmia that occurred during the operation. It was used to treat arrhythmia in 1963. It is currently a drug for the prevention and treatment of acute myocardial infarction and various heart diseases complicated by rapid ventricular arrhythmia. It is the ventricular arrhythmia of acute myocardial infarction. The drug of choice for premature beats, ventricular tachycardia and ventricular tremor. Therefore, the drug has the advantages of being safe, effective, and fast in action, and is widely used in the treatment of ventricular arrhythmias caused by various causes. In addition, this product is an amide local anesthetic and antiarrhythmic drug, and its anesthetic effect is twice that of procaine.
合成盐酸利多卡因时会产生盐酸利多卡因杂质E，需要对相应的盐酸利多卡因杂质E进行定性、定量检测，检测时需要用到相应的标准品。盐酸利多卡因杂质E标准品，又名2,2'-联氮基双(N-(2,6-二甲基苯基)乙酰胺)，其结构式如式Ⅰ所示，可用于检测盐酸利多卡因中是否含有盐酸利多卡因杂质E以及盐酸利多卡因杂质E的含量。该盐酸利多卡因杂质E收载于2013版欧洲药典中，要求控制在0.1％以内。Lidocaine hydrochloride impurity E will be produced during the synthesis of lidocaine hydrochloride, and the corresponding lidocaine hydrochloride impurity E needs to be qualitatively and quantitatively detected, and corresponding standard substances are required for detection. Lidocaine hydrochloride impurity E standard substance, also known as 2,2'-azinobis(N-(2,6-dimethylphenyl)acetamide), its structural formula is shown in formula I, which can be used to detect hydrochloric acid Does lidocaine contain lidocaine hydrochloride impurity E and the content of lidocaine hydrochloride impurity E. The lidocaine hydrochloride impurity E is recorded in the 2013 edition of the European Pharmacopoeia, and is required to be controlled within 0.1%.
现有技术中没有合成盐酸利多卡因杂质E的方法。因此提供一种盐酸利多卡因杂质E的合成方法，对杂质标准品的制备以及盐酸利多卡因的质量控制有重要意义。There is no method for synthesizing lidocaine hydrochloride impurity E in the prior art. Therefore, providing a synthetic method of lidocaine hydrochloride impurity E is of great significance to the preparation of impurity standards and the quality control of lidocaine hydrochloride.
发明内容Contents of the invention
本发明的目的是提供一种盐酸利多卡因杂质E的制备方法，可得到纯度较高的盐酸利多卡因杂质E，且盐酸利多卡因杂质E收率较高，盐酸利多卡因杂质E的纯化步骤较少。The purpose of this invention is to provide a kind of preparation method of lidocaine hydrochloride impurity E, can obtain the higher lidocaine hydrochloride impurity E of purity, and lidocaine hydrochloride impurity E yield is higher, the yield of lidocaine hydrochloride impurity E There are fewer purification steps.
为了实现以上目的，本发明采取的技术方案为：In order to achieve the above object, the technical scheme that the present invention takes is:
盐酸利多卡因杂质E的制备方法，包括以下步骤：将化合物1，即4-吗啉-3-苯胺，溶于溶剂，之后与化合物2在缚酸剂的作用下反应生成盐酸利多卡因杂质E，反应式如式1所示，The preparation method of lidocaine hydrochloride impurity E comprises the following steps: dissolving compound 1, i.e. 4-morpholine-3-aniline, in a solvent, and then reacting with compound 2 under the action of an acid-binding agent to generate lidocaine hydrochloride impurity E, the reaction formula is as shown in formula 1,
其中X为Cl、Br、OMe、OTs中的一种。Wherein X is one of Cl, Br, OMe, OTs.
进一步地，所述溶剂为二氯甲烷、二氯乙烷、N,N二甲基甲酰胺、二甲基亚砜中的一种或几种。Further, the solvent is one or more of dichloromethane, dichloroethane, N,N dimethylformamide, and dimethyl sulfoxide.
进一步地，所述化合物1与化合物2的摩尔比为1:0.9～1:1.5。Further, the molar ratio of compound 1 to compound 2 is 1:0.9˜1:1.5.
进一步地，所述缚酸剂为有机碱或无机碱，所述有机碱为乙胺、二乙胺、N,N-二异丙基乙胺、三乙胺中的一种或几种，所述无机碱为碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、碳酸铯中的一种或几种。Further, the acid-binding agent is an organic base or an inorganic base, and the organic base is one or more of ethylamine, diethylamine, N,N-diisopropylethylamine, and triethylamine, so The inorganic base is one or more of sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and cesium carbonate.
进一步地，所述化合物1与缚酸剂的摩尔比为1:1.5～1:3。Further, the molar ratio of the compound 1 to the acid-binding agent is 1:1.5-1:3.
进一步地，所述化合物1与化合物2反应时，在25～30℃条件下反应30～50min，之后升温至45～80℃反应1.5～3h，再升温至80～100℃反应2～4h。Further, when the compound 1 is reacted with the compound 2, the reaction is carried out at 25-30°C for 30-50 minutes, then the temperature is raised to 45-80°C for 1.5-3 hours, and then the temperature is raised to 80-100°C for 2-4 hours.
进一步地，所述化合物1与化合物2反应结束后加入水和乙酸乙酯，过滤，滤液分层后，有机层用饱和食盐水水洗、无水硫酸钠干燥，过滤并除去溶剂，即得盐酸利多卡因杂质E。Further, after the reaction of Compound 1 and Compound 2, water and ethyl acetate were added, filtered, and the filtrate was separated into layers, the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the solvent was removed to obtain lidocaine hydrochloride Caine impurity E.
本发明的有益效果：Beneficial effects of the present invention:
本发明的盐酸利多卡因杂质E的制备方法，采用4-吗啉-3-苯胺与取代的2,6-二甲苯基乙酰胺反应得到盐酸利多卡因杂质E，简单易操作，且反应较为安全，得到的产物纯度较高，收率较高。The preparation method of lidocaine hydrochloride impurity E of the present invention adopts the reaction of 4-morpholine-3-aniline and substituted 2,6-xylylacetamide to obtain lidocaine hydrochloride impurity E, which is simple and easy to operate, and the reaction is relatively Safety, the obtained product has higher purity and higher yield.
附图说明Description of drawings
图1为实施例1制备的盐酸利多卡因杂质E的1H NMR图；Fig. 1 is the1 H NMR figure of lidocaine hydrochloride impurity E prepared by embodiment 1;
图2为实施例1制备的盐酸利多卡因杂质E的液相色谱图以及峰表。Fig. 2 is the liquid chromatogram and peak list of lidocaine hydrochloride impurity E prepared in embodiment 1.
具体实施方式Detailed ways
下面将结合本发明实施例对本发明作进一步说明。The present invention will be further described below in conjunction with the embodiments of the present invention.
化合物1和化合物2反应生成盐酸利多卡因杂质E的反应式如式1所示：Compound 1 and compound 2 react to generate the reaction formula of lidocaine hydrochloride impurity E as shown in formula 1:
实施例1Example 1
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及35ml的溶剂DMF，之后室温搅拌条件下加入21.1g的化合物2a，即2-氯-N-(2，6-二甲苯基)乙酰胺，搅拌30min后，加入12.3g的二乙胺，25℃条件下反应40min，升温至60℃反应2h，再升温至90℃反应3h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得31.2g的盐酸利多卡因杂质E，纯度为98.2％，收率89.2％。反应式如式2所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the following steps: add 20g of compound 1, i.e. 4-morpholine-3-aniline, and 35ml of solvent DMF to a reactor with a thermometer and a stirring paddle , and then add 21.1 g of compound 2a, namely 2-chloro-N-(2,6-xylyl) acetamide, under stirring conditions at room temperature, and after stirring for 30 min, add 12.3 g of diethylamine, and react for 40 min at 25°C , raised the temperature to 60°C for 2 hours, then raised the temperature to 90°C for 3 hours, added water and ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, filtered, and removed the solvent in vacuo to obtain 31.2 g of lidocaine hydrochloride Impurity E has a purity of 98.2% and a yield of 89.2%. The reaction formula is shown in formula 2.
实施例2Example 2
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及35ml的溶剂二氯甲烷，之后室温搅拌条件下加入32.6g的化合物2b，即2-溴-N-(2，6-二甲苯基)乙酰胺，搅拌20min后，加入28.9g的N,N-二异丙基乙胺，30℃条件下反应50min，升温至45℃反应3h，再升温至100℃反应2h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得34.1g的盐酸利多卡因杂质E，纯度为98.6％，收率88.2％。反应式如式3所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the steps of: adding 20 g of compound 1, i.e. 4-morpholine-3-aniline, and 35 ml of solvent two to a reactor with a thermometer and a stirring paddle Chloromethane, then add 32.6g of compound 2b, namely 2-bromo-N-(2,6-xylyl)acetamide, under stirring at room temperature, and after stirring for 20min, add 28.9g of N,N-diisopropyl Ethylamine, react at 30°C for 50min, raise the temperature to 45°C for 3h, then raise the temperature to 100°C for 2h, add water and ethyl acetate, wash the organic layer with saturated saline, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo , to obtain 34.1 g of lidocaine hydrochloride impurity E, with a purity of 98.6% and a yield of 88.2%. The reaction formula is shown in formula 3.
实施例3Example 3
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及35ml的溶剂DMSO，之后室温搅拌条件下加入32.4g的化合物2c，即2-甲氧基-N-(2，6-二甲苯基)乙酰胺，搅拌40min后，加入34.0g的三乙胺，30℃条件下反应30min，升温至45℃反应1.5h，再升温至80℃反应4h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得35.0g的盐酸利多卡因杂质E，纯度为98.0％，收率90.6％。反应式如式4所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the following steps: add 20g of compound 1, i.e. 4-morpholine-3-aniline, and 35ml of solvent DMSO to a reactor with a thermometer and a stirring paddle , and then added 32.4 g of compound 2c, namely 2-methoxy-N-(2,6-xylyl) acetamide, under stirring conditions at room temperature, and after stirring for 40 min, added 34.0 g of triethylamine, at 30 ° C React for 30 minutes, raise the temperature to 45°C for 1.5h, then raise the temperature to 80°C for 4h, add water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo to obtain 35.0g of hydrochloric acid Lidocaine impurity E has a purity of 98.0% and a yield of 90.6%. The reaction formula is shown in formula 4.
实施例4Example 4
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及35ml的溶剂DMF，之后室温搅拌条件下加入36.6g的化合物2d，即2-对甲苯磺酰氧基-N-(2，6-二甲苯基)乙酰胺，搅拌40min后，加入20.5g的二乙胺，室温反应40min，升温至50℃反应2h，再升温至90℃反应4h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得34.2g的盐酸利多卡因杂质E，纯度为98.8％，收率90.7％。反应式如式5所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the following steps: add 20g of compound 1, i.e. 4-morpholine-3-aniline, and 35ml of solvent DMF to a reactor with a thermometer and a stirring paddle , then add 36.6g of compound 2d under stirring at room temperature, that is, 2-p-toluenesulfonyloxy-N-(2,6-xylyl) acetamide, after stirring for 40min, add 20.5g of diethylamine, room temperature React for 40 minutes, raise the temperature to 50°C for 2h, then raise the temperature to 90°C for 4h, add water and ethyl acetate, wash the organic layer with saturated saline, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo to obtain 34.2g of lidocaine hydrochloride Caine impurity E has a purity of 98.8% and a yield of 90.7%. The reaction formula is shown in formula 5.
实施例5Example 5
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及35ml的溶剂DMF，之后室温搅拌条件下加入33.2g的化合物2a，即2-氯-N-(2，6-二甲苯基)乙酰胺，搅拌30min后，加入24.6g的二乙胺，25℃条件下反应40min，升温至45℃反应2.5h，再升温至80℃反应4h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得34.0g的盐酸利多卡因杂质E，纯度为98.5％，收率88.0％。反应式如式2所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the following steps: add 20g of compound 1, i.e. 4-morpholine-3-aniline, and 35ml of solvent DMF to a reactor with a thermometer and a stirring paddle , then add 33.2g of compound 2a, namely 2-chloro-N-(2,6-xylyl)acetamide, under stirring conditions at room temperature, after stirring for 30min, add 24.6g of diethylamine, and react at 25°C for 40min , raised the temperature to 45°C for 2.5h, then raised the temperature to 80°C for 4h, added water and ethyl acetate, washed the organic layer with saturated brine, dried over anhydrous sodium sulfate, filtered, and removed the solvent in vacuo to obtain 34.0g of lidocaine hydrochloride Due to impurity E, the purity was 98.5%, and the yield was 88.0%. The reaction formula is shown in formula 2.
实施例6Example 6
本实施例的盐酸利多卡因杂质E的制备方法，包括以下步骤：向带有温度计和搅拌桨的反应器中加入20g的化合物1，即4-吗啉-3-苯胺，以及70ml的溶剂DMF，之后室温搅拌条件下加入33.2g的化合物2a，即2-氯-N-(2，6-二甲苯基)乙酰胺，搅拌30min后，加入23.7g的碳酸钠，28℃条件下反应50min，升温至45℃反应2.5h，再升温至80℃反应4h，加入水和乙酸乙酯，有机层用饱和食盐水洗，无水硫酸钠干燥，过滤，真空除去溶剂，得34.2g的盐酸利多卡因杂质E，纯度为98.0％，收率88％。反应式如式6所示。The preparation method of the lidocaine hydrochloride impurity E of the present embodiment comprises the steps of: adding 20 g of compound 1, i.e. 4-morpholine-3-aniline, and 70 ml of solvent DMF into a reactor with a thermometer and a stirring paddle Then, 33.2 g of compound 2a, namely 2-chloro-N-(2,6-xylyl)acetamide, was added under stirring at room temperature. After stirring for 30 min, 23.7 g of sodium carbonate was added, and the reaction was carried out at 28° C. for 50 min. Raise the temperature to 45°C for 2.5h, then raise the temperature to 80°C for 4h, add water and ethyl acetate, wash the organic layer with saturated brine, dry over anhydrous sodium sulfate, filter, and remove the solvent in vacuo to obtain 34.2g of lidocaine hydrochloride Impurity E has a purity of 98.0% and a yield of 88%. The reaction formula is shown in formula 6.
对比例comparative example
将化合物2a溶于溶剂，溶剂为1,4-二恶烷(1,4-Dioxane)、二甲基亚砜(DMSO)、N，N-二甲基甲酰胺(DMF)、四氢呋喃(THF)、甲苯(Toluene)或1,2二氯乙烷(DCE)，在氨和三乙醇胺的作用下，在25～80℃条件下反应24～28h，均得不到盐酸利多卡因杂质E。反应式如式7所示，反应条件如表1所示。式7所示的反应在表1的条件下均得不到盐酸利多卡因杂质E。Dissolve compound 2a in a solvent such as 1,4-dioxane (1,4-Dioxane), dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), tetrahydrofuran (THF) , toluene (Toluene) or 1,2 dichloroethane (DCE), under the action of ammonia and triethanolamine, reacted at 25-80°C for 24-28h, neither lidocaine hydrochloride impurity E could be obtained. The reaction formula is shown in Formula 7, and the reaction conditions are shown in Table 1. The reaction shown in formula 7 all can not obtain lidocaine hydrochloride impurity E under the condition of table 1.
表1对比例的反应条件The reaction condition of table 1 comparative example
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| CN202011039042.8ACN111995539B (en) | 2020-09-28 | 2020-09-28 | The preparation method of lidocaine hydrochloride impurity E |
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| PE01 | Entry into force of the registration of the contract for pledge of patent right | Denomination of invention:The preparation method of impurity E of lidocaine hydrochloride Granted publication date:20230811 Pledgee:Industrial and Commercial Bank of China Limited Zhengzhou Railway Branch Pledgor:ZHENGZHOU YUANLI BIOLOGICAL TECHNOLOGY CO.,LTD. Registration number:Y2025980028488 |